The CMV-Specific CD8<sup>+</sup> T Cell Response Is Dominated by Supra-Public Clonotypes with High Generation Probabilities
Evolutionary processes govern the selection of T cell clonotypes that are optimally suited to mediate efficient antigen-specific immune responses against pathogens and tumors. While the theoretical diversity of T cell receptor (TCR) sequences is vast, the antigen-specific TCR repertoire is restricte...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-08-01
|
| Series: | Pathogens |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-0817/9/8/650 |
| _version_ | 1797558434509357056 |
|---|---|
| author | Kilian Schober Pim Fuchs Jonas Mir Monika Hammel Lorenzo Fanchi Michael Flossdorf Dirk H. Busch |
| author_facet | Kilian Schober Pim Fuchs Jonas Mir Monika Hammel Lorenzo Fanchi Michael Flossdorf Dirk H. Busch |
| author_sort | Kilian Schober |
| collection | DOAJ |
| description | Evolutionary processes govern the selection of T cell clonotypes that are optimally suited to mediate efficient antigen-specific immune responses against pathogens and tumors. While the theoretical diversity of T cell receptor (TCR) sequences is vast, the antigen-specific TCR repertoire is restricted by its peptide epitope and the presenting major histocompatibility complex (pMHC). It remains unclear how many TCR sequences are recruited into an antigen-specific T cell response, both within and across different organisms, and which factors shape both of these distributions. Infection of mice with ovalbumin-expressing cytomegalovirus (IE2-OVA-mCMV) represents a well-studied model system to investigate T cell responses given their size and longevity. Here we investigated > 180,000 H2k<sup>b</sup>/SIINFEKL-recognizing TCR CDR3α or CDR3β sequences from 25 individual mice spanning seven different time points during acute infection and memory inflation. In-depth repertoire analysis revealed that from a pool of highly diverse, but overall limited sequences, T cell responses were dominated by public clonotypes, partly with unexpectedly extreme degrees of sharedness between individual mice (“supra-public clonotypes”). Public clonotypes were found exclusively in a fraction of TCRs with a high generation probability. Generation probability and degree of sharedness select for highly functional TCRs, possibly mediated through elevating intraindividual precursor frequencies of clonotypes. |
| first_indexed | 2024-03-10T17:31:22Z |
| format | Article |
| id | doaj.art-2cbc3e1c681242da809fd54d8066fd5b |
| institution | Directory Open Access Journal |
| issn | 2076-0817 |
| language | English |
| last_indexed | 2024-03-10T17:31:22Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pathogens |
| spelling | doaj.art-2cbc3e1c681242da809fd54d8066fd5b2023-11-20T10:00:44ZengMDPI AGPathogens2076-08172020-08-019865010.3390/pathogens9080650The CMV-Specific CD8<sup>+</sup> T Cell Response Is Dominated by Supra-Public Clonotypes with High Generation ProbabilitiesKilian Schober0Pim Fuchs1Jonas Mir2Monika Hammel3Lorenzo Fanchi4Michael Flossdorf5Dirk H. Busch6Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München (TUM), 81675 Munich, GermanyENPICOM B.V., 5211 AX ‘s-Hertogenbosch, The NetherlandsInstitute for Medical Microbiology, Immunology and Hygiene, Technische Universität München (TUM), 81675 Munich, GermanyInstitute for Medical Microbiology, Immunology and Hygiene, Technische Universität München (TUM), 81675 Munich, GermanyENPICOM B.V., 5211 AX ‘s-Hertogenbosch, The NetherlandsInstitute for Medical Microbiology, Immunology and Hygiene, Technische Universität München (TUM), 81675 Munich, GermanyInstitute for Medical Microbiology, Immunology and Hygiene, Technische Universität München (TUM), 81675 Munich, GermanyEvolutionary processes govern the selection of T cell clonotypes that are optimally suited to mediate efficient antigen-specific immune responses against pathogens and tumors. While the theoretical diversity of T cell receptor (TCR) sequences is vast, the antigen-specific TCR repertoire is restricted by its peptide epitope and the presenting major histocompatibility complex (pMHC). It remains unclear how many TCR sequences are recruited into an antigen-specific T cell response, both within and across different organisms, and which factors shape both of these distributions. Infection of mice with ovalbumin-expressing cytomegalovirus (IE2-OVA-mCMV) represents a well-studied model system to investigate T cell responses given their size and longevity. Here we investigated > 180,000 H2k<sup>b</sup>/SIINFEKL-recognizing TCR CDR3α or CDR3β sequences from 25 individual mice spanning seven different time points during acute infection and memory inflation. In-depth repertoire analysis revealed that from a pool of highly diverse, but overall limited sequences, T cell responses were dominated by public clonotypes, partly with unexpectedly extreme degrees of sharedness between individual mice (“supra-public clonotypes”). Public clonotypes were found exclusively in a fraction of TCRs with a high generation probability. Generation probability and degree of sharedness select for highly functional TCRs, possibly mediated through elevating intraindividual precursor frequencies of clonotypes.https://www.mdpi.com/2076-0817/9/8/650memory inflationpublic clonotypesgeneration probabilityT cell responseTCRconvergent recombination |
| spellingShingle | Kilian Schober Pim Fuchs Jonas Mir Monika Hammel Lorenzo Fanchi Michael Flossdorf Dirk H. Busch The CMV-Specific CD8<sup>+</sup> T Cell Response Is Dominated by Supra-Public Clonotypes with High Generation Probabilities Pathogens memory inflation public clonotypes generation probability T cell response TCR convergent recombination |
| title | The CMV-Specific CD8<sup>+</sup> T Cell Response Is Dominated by Supra-Public Clonotypes with High Generation Probabilities |
| title_full | The CMV-Specific CD8<sup>+</sup> T Cell Response Is Dominated by Supra-Public Clonotypes with High Generation Probabilities |
| title_fullStr | The CMV-Specific CD8<sup>+</sup> T Cell Response Is Dominated by Supra-Public Clonotypes with High Generation Probabilities |
| title_full_unstemmed | The CMV-Specific CD8<sup>+</sup> T Cell Response Is Dominated by Supra-Public Clonotypes with High Generation Probabilities |
| title_short | The CMV-Specific CD8<sup>+</sup> T Cell Response Is Dominated by Supra-Public Clonotypes with High Generation Probabilities |
| title_sort | cmv specific cd8 sup sup t cell response is dominated by supra public clonotypes with high generation probabilities |
| topic | memory inflation public clonotypes generation probability T cell response TCR convergent recombination |
| url | https://www.mdpi.com/2076-0817/9/8/650 |
| work_keys_str_mv | AT kilianschober thecmvspecificcd8supsuptcellresponseisdominatedbysuprapublicclonotypeswithhighgenerationprobabilities AT pimfuchs thecmvspecificcd8supsuptcellresponseisdominatedbysuprapublicclonotypeswithhighgenerationprobabilities AT jonasmir thecmvspecificcd8supsuptcellresponseisdominatedbysuprapublicclonotypeswithhighgenerationprobabilities AT monikahammel thecmvspecificcd8supsuptcellresponseisdominatedbysuprapublicclonotypeswithhighgenerationprobabilities AT lorenzofanchi thecmvspecificcd8supsuptcellresponseisdominatedbysuprapublicclonotypeswithhighgenerationprobabilities AT michaelflossdorf thecmvspecificcd8supsuptcellresponseisdominatedbysuprapublicclonotypeswithhighgenerationprobabilities AT dirkhbusch thecmvspecificcd8supsuptcellresponseisdominatedbysuprapublicclonotypeswithhighgenerationprobabilities AT kilianschober cmvspecificcd8supsuptcellresponseisdominatedbysuprapublicclonotypeswithhighgenerationprobabilities AT pimfuchs cmvspecificcd8supsuptcellresponseisdominatedbysuprapublicclonotypeswithhighgenerationprobabilities AT jonasmir cmvspecificcd8supsuptcellresponseisdominatedbysuprapublicclonotypeswithhighgenerationprobabilities AT monikahammel cmvspecificcd8supsuptcellresponseisdominatedbysuprapublicclonotypeswithhighgenerationprobabilities AT lorenzofanchi cmvspecificcd8supsuptcellresponseisdominatedbysuprapublicclonotypeswithhighgenerationprobabilities AT michaelflossdorf cmvspecificcd8supsuptcellresponseisdominatedbysuprapublicclonotypeswithhighgenerationprobabilities AT dirkhbusch cmvspecificcd8supsuptcellresponseisdominatedbysuprapublicclonotypeswithhighgenerationprobabilities |